A Review of Humoral Factors in Remote Preconditioning of the Heart

Abstract

A humoral mechanism of cardioprotection by remote ischemic preconditioning (RIP) has been clearly demonstrated in various models of ischemia–reperfusion including upper and lower extremities, liver, and the mesenteric and renal arteries. A wide range of humoral factors for RIP have been proposed including hydrophobic peptides, opioid peptides, adenosine, prostanoids, endovanilloids, endocannabinoids, calcitonin gene-related peptide, leukotrienes, noradrenaline, adrenomedullin, erythropoietin, apolipoprotein, A-I glucagon-like peptide-1, interleukin 10, stromal cell-derived factor 1, and microRNAs. Virtually, all of the components of ischemic preconditioning’s signaling pathway such as nitric oxide synthase, protein kinase C, redox signaling, PI3-kinase/Akt, glycogen synthase kinase β, ERK1/2, mitoKATP channels, Connexin 43, and STAT were all found to play a role. The signaling pattern also depends on which remote vascular bed was subjected to ischemia and on the time between applying the rip and myocardial ischemia occurs. Because there is convincing evidence for many seemingly diverse humoral components in RIP, the most likely explanation is that the overall mechanism is complex like that seen in ischemic preconditioning where multiple components are both in series and in parallel and interact with each other. Inhibition of any single component in the right circumstance may block the resulting protective effect, and selectively activating that component may trigger the protection. Identifying the humoral factors responsible for RIP might be useful in developing drugs that confer RIP’s protection in a more comfortable and reliable manner.

The Role of Natriuretic Peptides in the Regulation of Cardiac Tolerance to Ischemia/Reperfusion and Postinfarction Heart Remodeling

“…It is known that hemeoxygenase-1 (HO-1) promotes an increase in cardiac tolerance to ischemia/reperfusion. 151 It has been established the stimulation of peroxisome proliferator-activated receptor γ (PPARγ) increases myocardial resistance to ischemia/reperfusion. 159 It was shown that CNP induced activation of HO-1 expression in HUVECs.…”

“…It is known that transcription factors are involved in the cardioprotective effect of pre- and postconditioning. 105,151 This is primarily signal transducer and activator of transcription (STAT) and nuclear factor kappa B (NFκB). 151 There are no evince on involvement STAT in the infarct-reducing effect of natriuretic peptides.…”

“…It is well known that kinases play an important role in intracellular signaling and regulation of cardiac tolerance to ischemia/reperfusion. 105,151 So, it was established that the activation of a number of kinases (AMPK, PKC, PI3 K, Akt, ERK1/2, PKG) increases the resistance of the heart to ischemia and reperfusion. 105,151 At the same time, increased activity of glycogen synthase kinase 3b (GSK-3b) contributes to the occurrence of ischemic and reperfusion injury to the heart.…”

“…105,151 So, it was established that the activation of a number of kinases (AMPK, PKC, PI3 K, Akt, ERK1/2, PKG) increases the resistance of the heart to ischemia and reperfusion. 105,151 At the same time, increased activity of glycogen synthase kinase 3b (GSK-3b) contributes to the occurrence of ischemic and reperfusion injury to the heart. 105,151 Inhibition of protein kinase C (PKC) contributed to the disappearance of the cardioprotective effect of carperitide.…”

“…105,151 At the same time, increased activity of glycogen synthase kinase 3b (GSK-3b) contributes to the occurrence of ischemic and reperfusion injury to the heart. 105,151 Inhibition of protein kinase C (PKC) contributed to the disappearance of the cardioprotective effect of carperitide. 51 The hepatoprotective effect of cANP4-23 during hypoxia of liver is mediated via PKC-d activation.…”